2 Medical Research Council International Nutrition Group, Faculty of Epidemiology & Population Health, London School of Hygiene & Tropical Medicine, London, United Kingdom and Medical Research Council, Keneba, The Gambia

3 Epidemiology and Surveillance Unit, Centre of Infectious Disease Control, National Institute of Public Health and the Environment, Bilthoven, The Netherlands and Julius Center, University Medical Center Utrecht, Utrecht, The Netherlands

4 Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom

Abstract

Background

Identifying people at higher risk of developing tuberculosis with human immunodeficiency
virus (HIV) infection may improve clinical management of co-infections. Iron influences
tuberculosis (TB) pathogenesis, but understanding the exact mechanisms of how and
timing of when iron is involved remains challenging since biological samples are rarely
available from the disease susceptibility period due to the difficulty in predicting
in who and when, if ever, TB will develop. The objective of this research was to determine
how host iron status measured at HIV diagnosis and genotypes related to host iron
metabolism were associated with incident TB.

Methods

Archived clinical data, plasma and DNA were analyzed from 1139 adult participants
in a large HIV-1, HIV-2 and dual seroprevalent cohort based at the Medical Research
Council Laboratories in The Gambia. Incident pulmonary and/or extrapulmonary TB diagnoses
a minimum of 28 days after HIV diagnosis were independently re-confirmed using available
evidence (n=152). Multiple host iron status biomarkers, Haptoglobin and solute carrier
family 11, member 1 (SLC11A1) genotypes were modeled to characterize how indicators
of host iron metabolism were associated with TB susceptibility.

Conclusions

Evidence of host iron redistribution at HIV diagnosis was associated with incident
TB, and genetic influences on iron homeostasis may be involved. Low hemoglobin was
associated with subsequent diagnosis of TB, but when considered in combination with
additional iron status biomarkers, the collective findings point to a mechanism whereby
anemia and iron redistribution are likely due to viral and/or bacteria-driven processes
and the host immune response to infection. As a result, iron supplementation may not
be efficacious or safe under these circumstances. Clinical and nutritional management
of HIV and Mycobacterium tuberculosis co-infected individuals, especially in regions
where food insecurity and malnutrition co-exist, may be further improved when the
iron-related TB risk factors identified here are better understood and managed to
favor host rather than pathogen outcomes.